Dramatic changes in dietary patterns, characterized by excessive calorie intake from diets rich in fat and refined carbohydrates, are believed to be a major environmental driving force behind the rapid rise of cardio-metabolic diseases, such as atherosclerosis, obesity, and diabetes. Currently, very little is known about how dietary factors interact with host genetics and physiology to promote cardio-metabolic diseases. To address this problem, I employed a state-of-the-art systems genetics approach in the mouse that is capable of high-resolution genome-wide association mapping and systems-level integration of data across multiple scales of biology, including the genome, transcriptome, metabolome, and microbiome. The study is unprecedented in size, comprising 100 male and female inbred strains (>1400 mice) precisely phenotyped for hundreds of cardio-metabolic and molecular traits. The results show remarkable variation in obesity, insulin resistance, gut microbiota composition, and blood lipid levels in response to feeding a high-fat/high-sucrose diet. My genome- wide association studies (GWAS) have identified dozens of significant loci associated with cardio-metabolic traits. Some loci overlap with previously identified human GWAS loci, demonstrating for the first time that similar gene variants in mice and humans contribute to complex metabolic traits. To test the hypothesis that gene-environment interactions are strongly controlled by genetic factors, I propose two interrelated specific aims. In Aim 1, I will perform systems genetics analysis of high-dimensional datasets, including genome-wide transcriptome (from liver, adipose, and muscle), plasma metabolites, and gut microbiota. In Aim 2, I will validate significant genetic loci associated with obesity, a key cardio-metabolic disease, using gene-targeted mice. These aims will allow for a comprehensive integrative analysis to understand how host genetics and physiology intersect with diet to promote cardio-metabolic diseases. The proposal details a five-year integrated plan consisting of a two-year mentored training program (K99 Phase) followed by a three-year independent program (R00 Phase) for the development of an academic science research career. I have significant experience in atherosclerosis and metabolic diseases and plan to extend my scientific training in systems genetics and bioinformatics to study the genetic basis of gene-environment interactions in cardio-metabolic diseases. Along with the my mentor, Dr. Aldons J. Lusis, an internationally recognized expert in systems genetics and cardiovascular diseases, Drs. Peter Tontonoz, Karen Reue, Eleazar Eskin, and Rob Knight will serve as key advisors to provide relevant scientific mentorship and career guidance. Overall, the proposal is designed to advance my training in key scientific areas, develop critical skills (grant-writing, presentation, lab management, and others) to become a well-rounded scientific investigator, and foster my transition to an independent faculty position where I will setup an interdisciplinary research program focused on systems genetics, gene-environment interactions, and cardio-metabolic diseases.